DE2240224B2 - Process for the preparation of A3 ^ methyl-cephem-4-carboxylic acids - Google Patents

Description

From CA 8 17 883 it is known that one of R. B. Morin and colleagues, found rearrangement of penicillin sulfoxides into desacetoxycephalosporins (cf. US 32 75 626) can be improved by the fact that the esters in the presence of 5% acetic anhydride in Dimethylformamide rearranged; see also E. H. Flynn, Cephalosporins and Penicillins, 1972, p. 185.

In DE-OS 20 06 689 there is a further improvement the process for the preparation of desacetoxycephalosporanic acid esters by heating penicillin sulfoxide esters, especially penicillin V sulfoxide esters, in a tertiary carboxamide, preferably dimethylacetamide, Dimethylformamide or N-methyl-2-pyrrolidone, in the presence of a sulfonic acid and one water-binding agent described. The reaction proceeds using the example of penicillin V sulfoxide methyl ester schematically as follows:

C ₆ H ₅ OCH ₂ CON

Further processes for the preparation of deacetoxycephalosporanic acid esters by rearrangement of the corresponding 6-acylamidopenicillanic acid sulfoxide ester are described in DE-OS 20 11 351 and 20 11 376. To prepare the free acids or their salts, the ester group has to be split off in a further stage will. This inevitably leads to losses in yield.

When using acetic anhydride or acid catalyzed rearrangement to penicillin V sulfoxide found Morin et al., J. Am. Chem. Soc,

Vol. 91 (1969), p. 1401, the main product is the decarboxylated phenoxyacetamidocephalosporin:

H:: / \> ·
Nl - Y Y-CH ₃

HHS

N J-CQ ₁ N

CH ₃

The invention is based on the task of proceeding of 6-AcyIamidopenicillansäuresulfoxiden in the free Acid form directly the corresponding deacetoxycephalosporanic acids as such or in the form of their To prepare salts with bases in a one-pot process that is easy to carry out and in good yields runs. This object is achieved by the invention. The invention thus relates to the subject matter characterized in the patent claims. The process according to the prior art and the process according to the invention are tabulated below Procedures compared.

Known procedure Method according to the invention

100.0 penicillin (pen acid)

Al j 65% BE-PS 7 14 748
65.0 pen ester

A2j (100%) 65.0 PenSO ester

Ceph ester (in the reaction mixture) 52.0 Ceph ester (impure solid)

A4 I (90%)
46.8 Ceph ester (pure solid)

A5J 81%

37.4 1 ceph acid (pure solid)

100.0 penic acid

I (100%) Bl
100.0 PenSO acid

PenSO anhydride

A3

39.4 Ceph acid (pure, in reaction mixture)

. I 95% B3 37.4) Ceph acid (pure solid)

Remarks:

Al: This reaction stage is in DE-OS 20 11 351 and 20 11 376 are only described in general terms. In these DE-OS, preference is given to the 2,2,2-trichloroethyl esters. Therefore, the state of the art BE 7 14 748 called, in which the preparation of the 2,2,2-trichloroethyl ester of penicillin G in one Yield of 65% is described in this known process so occurs even before the Ring enlargement resulted in a loss of 35% of the starting material.

A2: The sulfoxide is not produced in 100 percent yield. So this one became Value in brackets. However, this level does not affect the comparison of the two Process, since in the process according to the invention the same step is carried out under similar conditions and no significant differences to be established. eo

A3: The step of converting the PenSO ester into the cephester was carried out with a yield of 80% specified. This value relates to the yield of impure end product which was obtained directly from the reaction mixture. It it is pointed out that the yields in Example 6 of DE-OS 20 11 351 and Example 68 of the DE-OS 20 11 376 are exceptionally high and not represent the rule. In DEOS 2011351 describe 17 of 21 examples and in DE-OS 20 11 376 66 of 73 examples with the implementation 2,2,2-trichloroethyl esters. In DE-OS 20 11 351 are uncorrected in 4 of the 17 examples and in DE-OS 2011 376 in 5 of the 66 examples Yields of over 80% indicated. It should be noted that sometimes two fractions to the Contribute to the exploitation value. Since only in 9 examples out of a total of 83 (17 + 66) a yield of above 80% is indicated, it seems justified to use the lower value of the yields of the known method to be set at 80%.

A4: The yields given in the DE-OS have to be corrected. Because of practical reasons it seems justified to introduce a purity correction factor of 0.90 with which the given yields must be multiplied.

A5: This stage is only described in general terms in the DE-OS. It is not a literature reference known, in which this stage is specifically described. The literature on this stage suggests that in usually the carboxyl protecting group remains untouched until subsequent reactions, namely the Cleavage of the side chain have been carried out.

Experience has shown that a yield of 8% when the trichloroethyl ester group is split off is extremely unlikely. It is more realistic to set this value at around 70%.
For the reasons given in the known method s yields of the individual steps in a total yield of 37.4% yields of pure end product

B1: The statements made above for A2 apply to this level.

B2: This stage is the inventive g? »wet procedures. The yield is based on the pure connection. It was determined microbiologically. The yield value of 39.4% was determined from calculated according to the reaction scheme

B3: The isolation is specifically described in Example 1. The microbiologically determined yield is 83%, while the yield of the compound actually isolated is 78% Isolation there is a loss of yield of at most about 5%.

The following can be seen from the reaction schemes above:

If the process of the present invention were run in an overall yield of 37.4%, it would be superior to the known process only in terms of yield. However, the procedure also brings one considerable procedural progress.

From DE-OS 20 06 689 it is known that the water of reaction is separated off when the ring is enlarged got to. This is especially necessary in the process according to the invention because the acid anhydride functions of the compounds used according to the invention are very sensitive to water. The use of such functional groups, on the other hand, have certain advantages, because they can easily be converted after implementation split off. This fact, too, is from the reactions described in AT 2 79 803, for example known The use of special organosilicon compounds of the type mentioned in the main claim for However, water separation during ring expansion cannot be considered obvious. In the Ring expansion of penicillin sulfoxides with anhydride carboxyl protecting groups has been carried out in extensive experiments studied a large number of compounds that bind water either chemically or physically. Examples of the compounds used are

Ethoxy acetylene. Molecular sieves,

Dicyclohexylcarbodiimide,

Phosphorus pentoxide, phenyltriethoxysilane,

Tetraethoxysilane, ethyltriethoxysilane,

Methyltriacetoxysilane,

Phenyltriacetoxysilane,

Triethyl orthoformate,

Dimethoxypropane, vinyl ethyl ether,

2,3-dihydro-4H-pyran and acetic anhydride.

50

55 Even when using excessive amounts of this compound to protect both the carboxyl group and to separate off the water, no ring expansion takes place unless certain bases are added in large excess to the reaction mixture. This embodiment is proposed in DE-OS 07 650. The ring expansion occurs, but the yields are lower than in the present processa

Two other strong prejudices against the use of other known control agents, such as bis (trimethylsilyl) acetamide (BSA) and related links had to be overcome.

a) Silylate these extremely active securing agents and deactivate acids that are used in the known processes, for example those in DE-OS 20 11 376 described method, as catalysts When converting penicillin G sulfoxide into dioxane with excess BSA and are suitable the usual amount of phosphoric acid monophenyl ester (one of the preferred catalysts) no trace of benzyl desacetoxycephalosporin could be found in the reaction mixture.

b) Another strong prejudice against the use of BSA and related securing agents for ring expansion of compounds such as penicillin G-sulfoxide can be found in the publication by G. E Gutowski, Tetrahedron Letters 1970, pages 1779 to 1782, and the corresponding US Pat. No. 3,719,667 . These publications show that penicillin sulfoxides are isomerized to the 6 * epimer by silylamides such as BSA. With the ring expansion of these 6'-epimers, the undesired epimers of the cephalosporins are obtained. The reaction time for the epimerization is 168 hours at room temperature. However, the reaction rate increases by a factor of 2 to 3 if the reaction temperature is increased ^{by 10 ° C.} Thus, at 80 ° C, the epimerization takes 15 to 150 minutes.

The foregoing shows that the excellent results in the invention Methods for ring expansion are not suggested by the prior art.

The acyl radical in the 6-acylamidopenicillanic acid sulphoxides used according to the method can be the same Meaning as in known cephalosporins or penicillins or their derivatives. For example it can be an alkanoyl radical with a maximum of 20 carbon atoms

No ring expansion occurred with any of the connections. From this it must be concluded that either the reactivity of the anhydrides 60 used to water is too high, so that the water-binding agents are ineffective, or that the water-binding agents Agents disrupt the ring expansion.

On the other hand, a customary silylating agent, such as trimethylchlorosilane, which _{comes into consideration as the agent of choice for silylation processes, is unsuitable for achieving the object of} the invention, at least without the application of additional precautionary measures.

Phenyl (lower) alkanoyl,
Phenoxy (lower) alkanoyl,
Phenyl (lower) alkyloxycarbonyl,
(lower) alkanoylaminocarbonyl or
(lower) alkoxy (lower) alkanoyl radical,

Phenoxyphenyl- (lower; r) -alkanoyl-,
Isoxazolylcarbonyl, benzoyl,
Naphthoyl, formyl, oxazolidinyl,
Phenyl - «- amino- (niedei) -alkanoy! -,
Thienyl or furyl (lower) alkanoyl,
Thienyl- or furyl-a-amino- (lower) -

alkanoyl,
Phenylthio (lower) alkanoyl,

2-Benzofuranyl- (lower) -alkanoyl-,
Benzenesulfonyl or
1-piperidinosulfonyl radical

mean. The phenyl radicals and heterocyclic radicals can optionally be replaced by halogen atoms, lower alkyl, protected carboxyl, phenyl (lower) alkoxy or protected amino radicals or nitro, Cyano, trifluoromethyl or methylthio groups may be substituted. The acyl radical can also be used together with the Nitrogen atom to which it is attached form a heterocyclic ring. Specific examples of acyl groups are the

Phthalimido, benzyloxycarbamoyl,

Phenylacetamido, phenoxyacetamido,

3-acetylureido, 2-phenoxypropionamido.

2-phenoxybutyramido,

2- phenoxyphenylacetamido,

5-methyl-3-phenyl-4-isoxazolcarboxamido,

5-methyl-3- (o-chlorophenyl) -4-

isoxazole carboxamido,
5-methyl-3- (2,6-dichlorophenyl) -4-

isoxazole carboxamido,
2,6-dimethoxybenzamido-,
2-ethoxy-1-naphthamido-,
2- (o-aminobenzamido) -phenyl-acetamido-

N-methyl,
2- (2-Amino-5-nitrobenzamido) -phenylacet-

amido-N-methyl-,
N-benzylformamido,
N-methyl-2-phenoxyacetamido,
N-methyl-2-phenylacetamido-,
N-ethyl-2-phenylacetamido-,
N-isobutyl-2-phenoxyacetamido-,
2-benzylidene-4,5-dioxo-3-oxazolidinyl-,
2-butyl succinimido,
2,2-dimethyl-5-oxo-4-phenyl-

1 -imidazolidinyl-phthalimido,
a-Amino-a- (1-cyclohexa-1,4-dienyl) -

acetamido,

a-aminophenyiacetamido-,
oc-amino-2-thienylacetamido-,
2-thienylacetamido-,
3-thienylacetamido-,
2-furylacetamido-,
4-chlorophenylacetamido-,
3-bromophenylacetamido-,
3-nitrophenylacetamido-,
4-nitrophenylacetamido-,
3-trifluoromethylphenylacetamido-,
4-cyanophenylacetamido,
4-methylthiophenylacetamido,
3-chlorophenylthioacetamido-,
2-benzofuranylacetamido-,
Benzenesulfonamido,
Benzenesulfonylaminoacetamido,
p-bromobenzenesulfonamido and
1 -piperidinosulfonamido radical

Preferred acyl radicals are the phenylacetamido and phenoxyacetamido groups. If necessary, for Production of a deacetoxycephalosporanic acid, in which the acyl radical is, for example, an α-aminophenylacetamido group means the free amino group in the side chain during the ring expansion reaction be protected for example by a benzyloxycarbonyl group, which is then split off again will. A free carboxyl group in the side chain can be protected, for example, by esterification. It is preferably produced by acid anhydride formation protected, with an additional amount of the reagent required for the acid anhydride formation of the with the carboxyl group linked to the thiazolidine ring is responsible.

When reacted with water, the organosilicon compounds used in step b) give neutral compounds which do not affect the course of the reaction and ^{do not impair the isolation of the 4 3} -7-acylamido-3-methylcephem-4-carboxylic acid.

Particularly preferred organosilicon compounds are N, O-bis (trimethylsilyl) acetamide and N, N'-bis (trimethylsilyl) urea, which formed very quickly with the water formed during the ring expansion of hexamethyldisiloxane and acetamide or urea react and so the cleavage of the acid anhydride function Prevent the water from widening the ring.

The amount of the organosilicon compound added to the reaction mixture in step b) must be so large be that the water formed during the reaction is completely removed and all free carboxyl groups in the 6-acylamidopenicillanic acid sulfoxide used be silylated. There are at least IV2 molar equivalents of the organosilicon compound per mole 6-acylamidopenicillanic acid sulfoxide required, namely 1/2 mole equivalent to silylate the carboxyl group and the remainder to remove the water formed.

Preferably there is at least 2 to 4 molar equivalents of the organosilicon compound per mole of 6-acylamidopenicillanic acid sulfoxide used.

In stage b) the acid can be added directly to the reaction mixture. The acid is advantageous with an organic nitrogenous base, for example an aliphatic, cycloaliphatic ^ aromatic or heterocyclic amine, especially hexamethylenetetramine, aniline, diphenylamine, N-methylaniline, Dimethylaniline, pyridine, a substituted pyridine, quinoline, a substituted quinoline, or isoquinoline a substituted isoquinoline, pyrazole, imidazole or a substituted imidazole. converted into a salt. as Substituents come, for example, lower alkyl, aralkyl, aryl or mono- or di- (lower) -alkylamino radicals in question. Specific examples of the substituted pyridines, quinolines, isoquinolines and imidazoles are the various picolines, 2-ethylpyridine, 2-propylpy- ' ridine, 2,3-dimethylpyridine, 2,5-dimethylpyridine, 2,6-dimethylpyridine, the various collidines, 2-dimethylaminopyridine, 3-methylisoquinoline and N-methylimidazole. Bases used with preference are pyridine, quinoline and imidazole and their derivatives. Preferably the base is used in excess with respect to the acid.

The salt formed from the acid and the base can be used in situ in the reaction mixture can be formed by first dissolving in an anhydrous, inert organic solvent dissolved 6-acylamidopenicilIansäuresulfoxid with the halide of the general formula R2-hai is implemented. The hydrogen halide formed in the process is then bound by the base, since the acid anhydride formation is smoother and the Penicillan sulfoxide ring is very sensitive to free, strong acids

The hydrogen halide initially formed in stage a) can represent the acid required for ring expansion of the penicflin sulfoxide or supplement it.
Preferred molar ratios of the

20th

JO

Compounds contained in the mixture are per 1 mole of δ-acylaminopenicillanic acid sulfoxide 1 to 4 moles of acid, ¹ A to 4 equivalents, preferably 1/3 to 1 equivalent of R 2 and at least 2 equivalents, preferably 3 to 7 equivalents of organosilicon compound; if the acid is used together with the base, Vio to 10 moles, preferably ¹ A to 4 moles of acid-base complex, ¹ A to 2 equivalents, preferably 1/3 to 1 equivalent R 2, at least 2 equivalents, preferably 3 to 7 Equivalent organosilicon compound and preferably an additional amount of the base itself, e.g. B. 1 to 10 mol, the amount of additional base preferably increasing in direct proportion to the amount of acid-base complex used. The expression "1 equivalent" is to be understood as the number of moles of R2-hal or organosilicon compound which is theoretically necessary for reaction with 1 mole of 6-acylaminopenicillanic acid sulfoxide.

The acid anhydride formation and the ring expansion reaction occur in an anhydrous organic Solvent carried out. Examples of such solvents are

Acetonitrile, chlorobenzene, toluene,

Diethylmethylsulfonamide, dimethylformamide,

Ν, Ν-dimethylacetamide, 1,2-dimethoxyethane,

Dioxane, triethylene glycol diethyl ether,

Tetraethylene glycol diethyl ether,

Nitrobenzene, benzyl cyanide,

Butyl acetate,

Isoamyl acetate,

Oxalic acid diethyl ester, anisole, benzene,

Carbon tetrachloride, dimethylsulfoxide,

Methyl ethyl ketone, methyl or

Ethyl isobutyl ketone and haloalkanes, such as

1,2-dichloroethane, 1,1-dichloroethane, ^i:>

1 - bromine-1-chloroethane, 1,2,3-trichloropropane,

Methylene chloride and chloroform.

Dioxane is preferably used.

The annular extension can be carried out at temperatures from 50 to 160 ° C, preferably 60 to HO ⁰ C are performed to 130 ° C and more preferably the 70th The reaction temperature is kept below 16O ⁰ C, to minimize the formation of decomposition products. In general, the reaction temperature and time are adjusted to one another in order to obtain good yields of ³ -7-acylamido-3-methylcephem-4-carboxylic acid. Longer reaction times are required at low temperatures and shorter reaction times are required at higher temperatures. For example, at 80, 90 and 100 ° C., the reaction times are about 24, 10 and 6 hours, respectively.

In a preferred embodiment of the process of the invention, per mole of 6-acylamidopenicillanic acid sulfoxide, for example benzylpenicillin sulfoxide, 1 to 4 moles of acid, preferably bromine or hydrogen chloride, 1.5 to 15 moles of base, preferably λ-picoline, the amount of base in each case being greater than that amount of acid, and 2 to 4 moles of NO-bis (trimethylsilyl) acetamide used in this case, the reaction at temperatures from 80 to 110 ⁰ C in an anhydrous inert solvent, preferably dioxane

In another preferred embodiment of the invention, large moles of 6-acylamidopenicillanic acid sulfoxide, V3 to 1 equivalent of acetyl bromide, 1.5 to 15 Mol base, preferably «-picoline, the amount of Base is in each case greater than that of the acid formed, and 1.5 to 3 mol of N, O-bis (trimethylsilyl) acetamide or N, N'-bis (trimethylsilyl) urea used.

For the hydrolysis in stage c), the reaction mixture can, after cooling, be extracted with water which has been adjusted to pH 7, for example with dilute aqueous potassium hydroxide solution. After washing with an organic solvent, such as butyl acetate, the 4 ³ -7-acylamido-3-methylcephem-4-carboxylic acid (e.g. the 7-phenylacetamido derivative) or its salt can be obtained from the aqueous solution as follows:

(a) by adding an aqueous solution of an acid and filtering off the precipitated deacetoxycephalosporanic acid;

(b) by extraction with an organic solvent at pH below 4.5 and evaporation of the extract, the acid crystallizing out;

(c) by adding n-butanol, removing the water and crystallizing the potassium salt of the acid from the butanol solution;

(d) by extraction with an organic solvent at a pH below 4.5, then Addition of an alkali metal salt, such as potassium acetate, or a solution of an alkali metal salt, e.g. B. Potassium 2-ethylhexanoate, or amine, e.g. B. triethylamine or cyclohexylamine, in an organic solvent and filtering off the precipitated Alkali metal or amine salt of the acid;

or

(e) by extraction with an organic solvent at pH below 4.5 and precipitation desacetoxycephalosporanic acid by adding an apolar organic solvent such as Diethyl ether or cyclohexane.

If the reaction is carried out in a water-miscible organic solvent, the 4 ³ -7-acylamido-3-methyl-cephem-4-carboxylic acid can be separated off by pouring the reaction mixture into water and adding an organic solvent. Sufficient water and organic solvent must be added to separate the mixture into two phases. The organic phase is re-extracted with water at pH 7, and the combined aqueous phases are washed with an organic solvent such as butyl acetate and then as under (a) to (e) above to obtain the ^ -desacetoxycephalosporanic acid or its salts treated. Another possibility for ending the reaction is to evaporate the organic solvent under reduced pressure, to dissolve the amorphous residue in a water-immiscible solvent and to add water. After adjusting the pH to 7, the organic phase is discarded. The aqueous solution is washed with an organic solvent and then treated as specified under (a) to (e) above. The reaction mixture can also be worked up by pouring into an aqueous acid solution of pH about 2 with stirring and then filtering off the deacetoxycephalosporanic acid.

The yield of 4 ³ -7-acylamido-3-methylcephem-4-carboxylic acid depends in the process according to the invention on the reagents and reaction conditions used. In general, however, yields of

more than 45 to 70 and even over 90%, based on 6-acylamidopenicillin sulfoxide, achieved.

In the process according to the invention, 6-acylamidopenicillanic acid sulfoxides are preferably used as starting compounds used that are made by fermentation, such as benzylpenicillin or phenoxymethylpenicillin, but other semisynthetically produced penicillins are also suitable.

The examples explain the invention. In the examples in which the yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is determined by a microbiological test, the acid can be obtained by treating the reaction mixture according to Example 1 below.

Example! !

10.5 g (30 mmol) of benzylpenicillin sulfoxide are successively mixed with 195 ml of dioxane, 25 ml (102 mmol) of N, O-bis (trimethylsilyI) acetamide, 6 ml (61 mmol) of λ-Ρϊ-colin and 5.2 ml a 5.8 m solution of "-Picolinhydrobromid in dichloromethane (30 mmol ot-Picolinhydrobromid) was added the trimethylsilyl derivative of Benzylpenicillinsulfoxid is formed in situ by refluxing for 6 hours at 102 ⁰ C, the reaction mixture is cooled to 2O ⁰ C and poured into 1500 ml of ice water. Then 650 ml of ethyl acetate and 50 ml of butyl acetate are added and the pH is adjusted to 7 with stirring with 4N potassium hydroxide solution. The organic phase is separated off and the aqueous phase is washed with 300 ml of ethyl acetate and 50 ml of butyl acetate. The previously separated organic phase and the organic washing liquids are combined. The combined extract is extracted with 200 ml of a 0.75 M potassium phosphate buffer of pH 7. The extract is combined with the original aqueous phase. This combined aqueous mixture contains 9.2 g of the potassium salt of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid, that is ^ -Benzyl-desacetoxycephalosporin, as can be determined by a microbiological test using Escherichia coli as the test microorganism. The yield is 83 percent of theory.

After adding 500 ml of butyl acetate to the aqueous solution, the mixture is stirred and the pH is adjusted to 2 with 4η-sulfuric acid. The mixture is then left to stand and the organic phase is separated off. The aqueous phase is extracted with 250 ml of butyl acetate. The combined butyl acetate extracts are filtered through a water-repellent filter. The aqueous phase, which still contains some 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid, is discarded. The Essigsäurebutylesterlösung is then anhydrous under vigorous stirring with 2.65 g (27 mmol), finely powdered potassium acetate was added after stirring for 3 hours at room temperature, the precipitate is filtered off, washed with a little acetate and at 30 ⁰ C under reduced pressure, dried to give 10.2 g Potassium salt of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid in a purity of 85 percent of theory, as can be determined by microbiological tests. The yield is 23.5 mmol, which corresponds to 78 percent of theory
Amax (H2O): 262nm (£ ü: 175).

The structure is confirmed by IR and KMR spectra.

KMR spectrum (as potassium salt in D ₂ O, values in ppm):

<5: 1.94 (s, 3);

2.99 (d, J = 18Hz, 1);

3.44 (d, J = 18Hz, 1);

3.62 (s, 2);

4.97 (d, J = 4.5 Hz, 1);

5.58 (d, J = 4.5Hz ₁ I);

7.27 (s, 5).

The sodium salt of 2,2-dimethyl-2-silapentyl-5-sulfonate is used as an internal standard.

Example 2

(a) 1.05 g (3 mmol) of benzyl penicillin sulfoxide are added to a mixture of 20 ml of a solution of 3.0 mmol Hydrogen bromide in dioxane and 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide were added. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The reaction mixture is raised to 102 ° C warmed up. The course of the reaction is determined by thin layer chromatography.

After 6 hours there is no longer any penicillin sulfoxide present in the reaction mixture. Samples of 5 ml each are taken and poured into 35 ml of a 0.75 M potassium phosphate buffer with a pH of 7. The aqueous solution is washed with 10 ml of ethyl acetate and diluted with 50 ml of water. The amount of the potassium salt of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid formed in the aqueous solution is determined by a direct microbiological test using Escherichia coli as the test microorganism. After 6 hours the yield of 4 ³ -7-phenylacetamido-deacetoxycephalosporanic acid is 47 percent of theory.

(b) The experiment described under (a) is repeated, but using 18 ml of toluene and 2 ml of a 1.5 M solution of hydrogen bromide in dioxane instead of the 20 ml of dioxane. The yield of 4 ³ -7-phenylacetamido-deacetoxycephalosporanic acid determined by microbiological means is 46 percent of theory.

(c) Proceed as in (a), but use an additional amount of 03 ml (9 mmol) «-picoline. The microbiologically determined yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 82 percent of theory.

Example 3

1.05 g (3 mmol) of benzylpenicillin sulfoxide are successively mixed with 20 ml of dioxane, 3.2 ml (13 mmol) of NO-bis-itrimethylsilyO-acetamide and 0.57 g (3 mmol) of p-toluenesulfonic acid situ. After 6 hours of heating the reaction mixture to 101 ⁰ C, the sulfoxide is completely reacted by working up the reaction mixture according to Example 2 of the theory are obtained 4 ³ -7-phenylacetamido-desacetoxycephaJosporansäure in a yield of 41 percent (determined microbiologically).

Example 4

(a) A mixture of 2.1 g (6 mmol) of benzyl penicillin sulfoxide, 20 ml chloroform, 5 ml (20 mmol) N, O-bis (trimethylsilyl) acetaniide and 2 ml of a 33-M solution of it-picoline hydrochloride (6.6 mmol) in dichloroethane Heated to 84 ° C. for 24 hours. The yield increases

^^ - Phenylacetamidodesacetoxycephalosporanic acid is 53% of theory, as shown in Example 2 microbiological way can be determined.

Example 5

A mixture of 1.05 g (3 mmol) of benzyl penicillin sulfoxide, 10 ml of benzyl cyanide, 10 ml (100 mmol) of a-picoline, 3 ml of a 3.3 M solution of α-picoline hydrochloride (10mmoI) in 1,2-dichloroethane and 2.5 ml (10 mmol) N, O-bis (trimethylsilyl) acetamide is heated to 95 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide arises in situ. After 6 hours the yield of dM-phenylacetamido-desacetoxycephalosporanic acid is 48 percent of the theory, as can be determined according to example 2 in a microbiological way. 1 ■>

Example 6

The procedure is as in Example 5, but 15 ml of benzyl cyanide and 5 ml (50 mmol) of ix-picoline are used. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of / d ³ -7-phenylacetamidodesacetoxycephalosporanic acid after heating to 95 ° C. for one hour is 48 percent of theory, as can be determined according to Example 2.

Example 7

25th

The procedure is as in Example 5, but 17.5 ml of benzyl cyanide, 2.5 ml (25 mmol) of α-picoline and 2 ml of a 3.3 M solution of -picoline hydrochloride (6.6 mmol) in 1 are used , 2-dichloroethane. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid after heating at 95 ° C. for 6 hours is 48 percent of theory, as can be determined in accordance with Example 2.

Example 8

A mixture of 1 g (3 mmoles) of benzyl penicillin sulfoxide, 15 ml of benzyl cyanide, 7.2 ml (72 mmoles) of pyridine. 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.27 ml (1 mmol) of a 3.3 M solution of-picoline hydrochloride are heated to 90.degree. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. After 6 hours, the yield of 4 ³ -7-phenylacetamido-deacetoxycephalosporanic acid is 38 percent of theory, as can be determined according to Example 2.

Example 9

A mixture of 1.05 g (3 mmol) of benzyl penicillin sulfoxide, 20 ml of benzyl cyanide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.24 g (1.5 mmol) of pyridine hydrobromide is made 90 ° C heated. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. After 10 hours, the yield of 4 ³ -phenylacetamido-desacetoxycephalosporanic acid is 54 percent of theory, as can be determined by microbiological means

Example 10

Example 11

60

The procedure is as in Example 9, but using 0.48 g (3 mmol) of pyridine hydrobromide and adding 03 ml (3 mmol) of a-picoline. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. After 1 Ostfindigem heating to 90 ⁰ C, the yield of A ³ -7- phenylacetamido-deacetoxycephalosporanic acid is 59 percent of theory, as can be determined by microbiological means

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethyl silyl) acetamide, 0.48 g (3 mmol) of pyridine hydrobromide and 0, 3 ml (3 mmol) of a-picoline is heated to 85 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. After 22 hours, the reaction mixture is poured into 150 ml of 0.75 M potassium phosphate buffer of pH 7 and washed with 50 ml of chloroform. The pH of the aqueous phase is adjusted to 2 in the presence of 50 ml of ethyl acetate. The ethyl acetate phase is washed with water and dried over anhydrous sodium sulfate.After evaporation of the ethyl acetate, 1 g of 4 ³ -7-phenylacetamidodeacetoxycephalosporanic acid is obtained in a purity of 56 percent, as can be determined by nuclear magnetic resonance spectroscopy using 2,6-dichloroacetophenone as the internal standard .

Example 12

A mixture of 1.05 g (3 mmoles) of benzylpenicillin sulfoxide, 20 ml of dioxane, 2.5 ml (10 mmoles) of N, O-bis (trimethylsilyl) acetamide, 0.5 ml (3 mmoles) of a 6-M solution of α-picoline hydrobromide in dichloromethane and 0.6 ml (6 mmol) of α-picoline is heated to 102 ° C. while stirring. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. After 6 hours, the reaction mixture is poured into a mixture of 200 ml of a 0.75 M phosphate buffer with a pH of 7 and 50 ml of ethyl acetate. The buffered aqueous phase is washed with 50 ml of ethyl acetate. The aqueous phase is adjusted to pH 2 and extracted twice with 100 ml of ethyl acetate each time. After drying over magnesium sulfate, the ethyl acetate is evaporated off under reduced pressure. The residue (1.07 g) contains 70 percent / d ³ -7-phenylacetamido-deacetoxycephalosporanic acid, as can be determined by UV and CMR spectroscopy. The yield is 2.25 mmol, which is 75 percent of theory

Example 13

0.64 g (33 mmol) of triethylbromosilane are added to a mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide. 20 ml of dioxane and 0.9 ml (9 mmol) of a-picoin are added. After stirring for 30 minutes, the triethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ, which can be confirmed by nuclear magnetic resonance spectroscopy is heated to 102 ° C. for 4 hours. After treating the reaction mixture according to Example 2, 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is obtained in a yield of 73 percent of theory, as can be determined by microbiological means

Example 14

A mixture of 2 ml (3 mmol) of a 1.5 M solution of hydrogen halide in benzyl cyanide, £ 5 ml (10 mmol) N, O-bis (trimethylsilyr) acetamide and 0.9 ml (9 mmol) «-Picoline in 19 ml of benzyl cyanide is added with 1.05 g (3 mmol) Bezylpenicfllinsulfoxid added The mixture is heated to 95 ° C for 6 hours. The yield of , d ^ -Phenvlacetamido-desacetoxvcenhalnsnoranoic acid

is 48 percent of theory as shown in the example 2 can be determined.

Example 15

(a) 1.05 g (3 mmoles) of benzyipenicillin sulfoxide 18 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsyl) acetamide and 0.9 ml (9 mmol) of a-picoline were added. After a few minutes, 2 ml of a 1.5 m solution of hydrogen bromide (3 mmol) in dioxane are added, and the resulting mixture is heated to 101 ° C. for 6 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ Reaction mixture according to Example 2 is obtained zP ^ -phenylacetamido-desacetoxycephalosporanic acid in a yield of 97 percent of theory, as can be determined in a microbiological way

(b) A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyI) acetamide, 0.3 ml (3 mmol) of a-picoline and 0, 25 ml (1.5 mmol) of a 6 M solution of α-picoline hydrobromide in 20 ml of dioxane is refluxed for 1/2 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of 4 ³ -7-phenylacetamidodesacetoxycephalosporanic acid is 82 percent of theory, as can be determined by microbiological means.

(c) The procedure is as in (b), but using 700 mg (3 mmol) of picric acid instead of a-picolin hydrobromide. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of <d ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 47 percent of theory, as can be determined by microbiological means.

Example 16

35

(a) 530 mg (1.5 mmol) of benzylpenicillin sulfoxide are suspended in 10 ml of dioxane. After the addition of 0.45 ml (4 ^ mmol) of a-picoline, the clear solution is cooled to 0 ⁰ C. 0.05 ml (0.5 mmol) of phosphorus tribromide are added with vigorous stirring. The mixture is stirred at 0 ° C. for 30 minutes. The anhydride of benzylpenicillin sulfoxide and phosphorus tribromide is formed in situ. 0.9 ml (3.5 mmol) of N, O-bis (trimethylsilyl) acetamide are then added. After refluxing for 4 1/2 hours, the yield is on zl ³ -7-phenylacetamido-deacetoxycephalosporanic acid 85 percent of the theory, as can be determined by microbiological means.

(b) Proceed as under (a), but use 0.05 ml (0.5 mmol) of acetyl bromide instead of phosphorus tribromide. In this case, the acetyl anhydride of benzylpenicillin sulfoxide is formed as an intermediate product. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 87 percent of theory, as can be determined by microbiological means.

(c) The procedure is as in (b), but the acetyl bromide is added at room temperature. The yield of ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 83 percent of theory, as can be determined by microbiological means

(d) Proceed as under (b), but use 036 ml (4.5 mmol) of pyridine instead of Λ-picoline. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 94 percent of theory.

(e) Proceed as under (d), but use 0.07 ml (1.0 mmol) of acetyl bromide. The yield of J ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 92 percent of theory.

(f) Proceed as under (d), but use 0.14 ml (2.0 mmol) of acetyl bromide. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 93 percent of theory.

(g) The procedure is as in (d), but 0.05 ml of oxalyl bromide is used instead of acetyl bromide. In this case, the oxalyl anhydride of benzylpenicillin sulfoxide is formed as an intermediate product. The yield of ³ -7-phenylacetamido-deacetoxycephalosporanic acid is 69 percent of theory.

(h) Proceed as under (e), but use 10 ml Tohiol as a solvent instead of dioxane. The acetyl anhydride of benzylpenicillin sulfoxide is formed in situ. The yield of ^ - ^ - phenylacetaraido-desacetoxycephalosporanic acid is 76 percent of theory.

(i) Proceed as under (e), but use 10 ml butyl acetate instead of dioxane. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 78 percent of theory.

Example 17

A solution of 10.5 g (30 mmol) Benzylpenicillinsulfoxid in 150 ml of dioxane and 7.2 ml (90 mmol) of pyridine is cooled to ⁰ C 6. After adding a solution of 1.4 ml (18.5 mmol of acetyl bromide in 50 ml of dioxane), the mixture is stirred for 3½ minutes at 5 ° C. The acetyl anhydride of benzylpenicillin sulfoxide is formed in situ. 18 ml (70 mmol) of N, O- Bis (trimethylsilyl) acetamide is added and the reaction mixture is refluxed for 4 1/2 hours After cooling, the mixture is poured into 1 liter of 0.2 M potassium phosphate buffer, pH 7. After the pH has been adjusted Value with 4N potassium hydroxide solution to 7, 600 ml of butyl acetate are added. The mixture is shaken and the two phases are separated with the aid of a separating funnel. The aqueous phase is washed with 400 ml of butyl acetate. The combined butyl acetate phases are mixed with 500 ml of a 0 , 75-m potassium phosphate buffer of pH 7 is extracted, and the extracts are combined with the original aqueous phase.

The combined aqueous solutions contain 9.1 g of the potassium salt of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid (82 percent of theory), as can be determined by UV spectroscopy and by a microbiological test using Escherichia coli as the microorganism.

The potassium salt of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is isolated according to Example 1. 11.1 g of product of 67 percent purity are obtained, as can be determined by microbiological means (yield 75 percent of theory).

Example 18

(a) 530 mg (1.5 mmol) of benzylpenicillin sulfoxide are suspended in 10 ml of dioxane. After adding 0.45 ml (43 mmol) of A-picoline, the clear solution is ^{cooled to 0} ° C. With vigorous stirring, 0.05 ml is added Introduced (0.7 mmol) of acetyl bromide, and the mixture is stirred for 30 minutes at 0 ° C. The acetyl anhydride of benzylpenicillin sulfoxide is formed in situ.

135 g (6.6 mmol) of N, N'-bis (trimethylsilyl) urea are then added At reflux, zP-7-phenylacetamido-desacetoxycephalosporanic acid is obtained in a yield of 54 Percent of the theory, as can be determined in a microbiological way.

909 530/148

(b) Proceed as under (a), but use 0.05 ml (0.5 mmol) of phosphorus tribromide instead of acetyl bromide. In this case, the anhydride of benzylpenicillin sulfoxide and phosphorus tribromide is formed as an intermediate product. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporai acid is 33 percent of theory, as can be determined by microbiological means

(c) The procedure is as under (a), but using 10 ml of acetic acid butyester instead of dioxane and 0.12 ml (1.5 mmol) of acetyl bromide. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 54 percent of theory.

(d) Proceed as under (a), but use 036 ml (4.5 mmol) pyridine instead of α-picoline and 0.22 ml (2.5 mmol) trimethylbromosilane instead of acetyl bromide.

The trimethylsilyl derivative is used as an intermediate

Table I.

10

15 formed by benzylpenicillin sulfoxide The yield of • d ^ -phenylacetamido-desacetoxycephalospo ransäure is 80 percent of theory.

(e) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 760 mg (3.7 mmol) of N, N'-bis (trimethylsily]) urea are suspended in 10 ml of toluene. Then 0.12 ml (1.5 mmol) of pyridine and 0.12 ml (1.0 mmol) benzoyl bromide and the mixture for 5 hours at 100 ° C heated When intermediate the benzoyl anhydride formed by Benzylpenicillinsulfoxid the yield of 4 ³ -7-Phenylacetamidodesacetoxycephalosporansäure is 57 percent of theoretical, as can be determined in a microbiological way

(f) Proceed as under (e), but use instead other acid derivatives other than benzoyl bromide. The results are compiled in the following table

Acid derivative

Amount of acid Yield to derivative 4 ³ -7-phenylacetamido- desacetoxycephalosporan acid (mmol) (%) 1.0 67 1.0 67 1.0 75 0.65 67 0.37 81 0.34 40 0.25 73 0.25 82 0.2 82 0.33 75 0.37 74 0.2 56

Trichloroacetyl bromide

Trichloroacetyl chloride

Propionyl bromide

Thionyl bromide

Boron tribromide

Aluminum tribromide

Silicon tetrabromide

Germanium tetrabromide

Phosphorus pentabromide

Phosphorus oxybromide

Phosphorothiobromide

Tungsten tabromide

Example 19

525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.4 g (7 mmol) of N, N'-bis (trimethylsilyl) urea are suspended in 10 ml of dioxane. The suspension is mixed with 0.35 ml (2 mmol) of a 6 M solution of-picoline hydrobromide in dichloromethane and heated to 100 ° C. for 4 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of 4 ³ -7-phenylacetamido-deacetoxycephalosporanic acid is 80 percent of theory, as can be determined according to Example 2.

Example 20

(a) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.05 g (5 mmol) of N, N'-bis (trimethylsilyl) urea are suspended in 10 ml of dioxane. The suspension is mixed with 0.25 ml (3 mmol) of pyridine and 0.15 ml (1.6 mmol) of trimethylbromosilane and heated to 100 ° C. for 4/2 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of b5 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 85 percent of theory, as can be determined by microbiological means.

(b) Proceed as under (a), but use 0.16 ml (1.6 mmol) Λ-picoline instead of pyridine. The yield is 85 percent of theory.

(c) Proceed as under (a), but use 0.83 ml (3.4 mmol) of N, O-bis (trimethylsilyl) acetamide instead of N, N'-bis (trimethylsilyl) urea. The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 69 percent of theory, as can be determined by microbiological means.

Example 21

525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.05 g (5 mmol) of N, N'-bis (trimethylsiryl) urea are suspended in 10 ml of acetic acid butyester. 0.23 ml (2.3 mmol) of Λ-picoline and 0.2 ml (2.2 mmol) of trimethylbromosilane are added to the suspension. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. After 4½ hours of heating at 100 ° C., the yield of d ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 78 percent of theory, as can be determined by microbiological means.

Example! 22nd

A mixture of 1.05 g (3 mmol) Benzylpenicillinsulfoxid, 3.1 ml (15 mmol) of hexamethyldisilazane, 6 ml of a 0.5 m solution of hydrogen bromide in dioxane and 14 ml of dioxane is 4V2 hours at 100 ⁰ C. The heated trimethylsilyl Benzylpenicillin sulfoxide is formed in situ. The yield of 4 ³ -7-phenylacetamidodesacetoxycephalosporanic acid is 48 percent of theory, as can be determined in accordance with Example 2 by microbiological means.

Example 23

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 18 ml of dioxane, 03 ml (9 mmol) of picoline, 2.6 g (10 mmol) of NO-bis-itrimethylsilylJ-trifluoroacetamide and 2 ml of a 1.5-m The solution of hydrogen bromide in dioxane is refluxed for 4 1/2 hours. The trimethylsilyl derivative of benzylpenicil unsulfoxide is formed in situ. The yield of d ³ -7-phenylacetamidodeacetoxycephalosporanic acid is 73 percent

Table II

Theory, as can be determined in a microbiological way

Example 24

1.05 g (3 mmol) of benzyl penicillin sulfoxide are used in 15 ml of dioxane suspended The suspension is mixed with 23 ail (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 1.2 ml (9 mmol) of 2-methylquinine and 6 ml of a 0.5-m A solution of hydrogen bromide in dioxane is added

ι »mixture is 4 '/ 2 hours at ⁰ C heated 10G The trimethylsilyl derivative of Benzylpenicillinsulfoxid is formed in situ, the yield of 4 ³ -7-Phenylacetamidodesacetoxycephalosporansäure is 49 percent of theoretical, as in Example 2 using

i: i Escherichia coli identified as the test microorganism can be.

This attempt is repeated several times using some other base instead of 2-methylquinoline repeated The results are in the following table

2i) compiled

base Amount of base Yield to 4 ³ -7-phenylacetamido- desacetoxycephalospoian- acid (mmol) (%) 1. Diphenylamine 3 54 2. aniline 9 58 3. N-methylaniline 9 53 4th Hexamethylenetetramine 2.25 73 5. 3-methylpyridine 9 75 6th 4-methylpyridine 9 82 7th 2,3-dimethylpyridine 9 80 8th. 2,6-dimethylpyndine 9 52 9. 2-ethyl pyridine 9 68 10. 2-propyl pyridine 9 85 11th 4-benzyl pyridine 9 75 12th 4-phenylpyridine 9 81 13th 2-dimethylaminopyridine 9 84 14th 1,3,5-collidine 9 84 15th Quinoline 9 84 16. Isoquinoline 9 89 17th 3-methyl-isoquinoline 9 72 18th Pyrazole 9 54 19th Imidazole 3 69 20th N-methylimidazole 3 87

Example 25

(a) A mixture of 525 mg (1.5 mmol) benzylpenicillin sulfoxide, 10 ml toluene, 0.12 ml (1.5 mmol) pyridine, 1.45 ml (9 mmol) N-methyl-N-trimethylsilylacetamide and 0, 35 ml of a 6 m solution of "picoline hydrobromide in dichloromethane for 5 hours at 100 ⁰ C heated. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield of -d ^ -phenylacetamido-desacetoxycephalosporanic acid is 58 percent of theory, as can be determined by microbiological means

(b) Proceed as under (a), but use 1.7 ml

(9.2 mmol) N-methyl-N-trimethyisilyl trifluoroacetamide instead of N-methyl-N-trimethylsilylacetamide. the

Yield of 4 ³ -7-phenylacetamido-desacetoxycephalo-

sporic acid is 86 percent of theory.

Example 26

6!:> A mixture of 1.05 g (3 mmol) of benzyl penicillin sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.6 ml (6 mmol) of Λ-picoline and 0.5 ml of a 6 m solution of Λ-picolin hydrobromide in methylene chloride is with

20 ml of dioxane are added and the mixture is heated under reflux for 4 1/2 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide is formed in situ. The yield at id -'- y-phenylacetamido-desacetoxycephalosporanic acid is 82 percent of theory, as can be determined according to Example 2 in a microbiological way.

This experiment is repeated several times, with other solvents instead of dioxane! be used. The results are in the table below compiled

Table UI example Yield of solvent ^ ³ -7-phenylacetamido- desacetoxycephalosporan- acid 40 1,2,3-trichloropropane 41 toluene 44 Ν, Ν-dimethylacetamide 49 Diethylmethylsulfonamide 52 Chlorobenzene 60 Isoamyl acetate 64 Butyl acetate 82 Oxalic acid diethyl ester 81 Anisole 58 1,2-dimethoxyethane 81 Tetraethylene glycol dimethyl ether 64 Triethylene glycol dimethyl ether 27

13 g (3 mmol) of 2-ethoxynaphthylpenicillin sulfoxide, 2.5 ml (10 mmol) N.O-Bis-OrimethylsilyO-acetamide,

03 ml (3 mmol) a-picoline and 0.25 m! (1.5 mmol) one A 6-m solution of a-picoline hydrobromide in methylene chloride is dissolved in 20 ml of dioxane. The trimethylsilyl derivative of 2-ethoxynaphthylpenicillin sulfoxide is formed in situ. The mixture is taking 4 '/ 2 hours Heated to reflux and then in a cold mixture of 200 ml of a 0.75 M potassium phosphate buffer of pH 7 and 50 ml of ethyl acetate poured. After adjusting the pH to 7 with

4 N potassium hydroxide solution, the mixture is placed in a separatory funnel, shaken and allowed to stand. The aqueous phase is washed with 50 ml of ethyl acetate and, after the pH has been adjusted with 4 η-sulfuric acid, extracted twice with 100 ml of ethyl acetate each time. After drying over magnesium sulfate, the ethyl acetate is evaporated off under reduced pressure. The dried residue (490 mg) consists of 80 percent / d ³ -7- (2-ethoxynaphthamido) -desacetoxyc: ephalosporanic acid, as can be determined by CMR spectroscopy using 2,6-dichloroacetophenone as internal standard. The yield is 31 percent of theory.

Example 28

The procedure is as in Example 27, but using 1.1 g (3 mmol) of phthalunidopenicillin sulfoxide and replacing the a-picoline hydrobromide solution and the "picoline" with 0.5 ml (3 mmol) of a 6-m solution of a-picoline hydrobromide in methylene chloride. The trimethylsilyl derivative of phthalimidopenicillin sulfoxide is formed in situ. The reaction mixture is treated as in Example 27. 880 mg of 4 ³ -7-phthalimido-deacetoxycephalosporanic acid are obtained in a purity of 84 percent. The yield is 72 percent of theory.

Example 29

The procedure is as in Example 27, but 1.3 g (3 mmol) of benzenesulfonamidomethylpenicillin sulfoxide are used. The trimethylsilyl derivative of benzenesulfonamidomethylpenicillin sulfoxide is formed in situ. You get 13 g ^^ - Benzenesulfonamidomethyl-deacetoxycephalosporanic acid in a purity of 63 percent. the Yield is 66 percent of theory.

Example 30

(a) 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide are mixed with 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (irimethylsilyl) acetamide, 0.6 ml (6 mmol) of a-picoline and 03 ml (3 mmol) of a 6 m solution of ix-picoline hydrobromide in methylene chloride were added. The trimethylsilyl derivative of phenoxymethylpenicillin sulfoxide is formed in situ. The mixture is refluxed for 4 1/2 hours and then treated as in Example 2. The yield of 4 ³ -7-phenoxyacetamido-desacetoxycephalosporanic acid is 71 percent of theory, as can be determined by a direct microbiological test using Escherichia coli as the test microorganism

(b) The procedure is as under (a), but the reaction mixture is worked up according to Example 27. 860 mg / 4 ³ -7-phenoxyacetamido-desacetoxycephalosporanic acid are obtained in a purity of 85 percent of theory, as shown by CMR spectroscopy using 2,6-dichloroacetophenone as internal Standard gives the yield is 70 percent of theory.

Example 31

A suspension of 135 g (3 mmol) of the cyclohexylammonium salt of benzylpenicillin sulfoxide in 15 ml Dioxane is mixed with 2.8 ml (11 mmol) of N, O-bis (trimethylsilyl) acetamide and 6 ml of a 0.5 m solution of Hydrogen bromide in dioxane is added Lyl derivative of benzylpenicillin sulfoxide is formed in situ. The mixture is heated under reflux for 4 1/2 hours. The yield of / 4 ³ -7-phenylacetamido-deacetoxycephalosporanic acid is 55 percent of theory, as determined by microbiological means lets go

Example 32

(a) A solution of 03 ml (3 mmol) of acetyl bromide in 5 ml of 1,2-dichloroethane becomes a solution of 1.1 g (3 mmol) phenoxymethyl penicillin sulfoxide and 0.72 ml (9 mmol) of pyridine in 20 ml of 1,2-dichloroethane.

After Istündieem stirring at 0 ⁰ C, the mixture is

filtered off and evaporated to dryness. The residue obtained is 1.08 g (2.6 mmol) of mixed anhydride from Phenoxymethylpenicillin and acetic acid in the form of a foam-like solid.

IR spectrum (in CHCI ₃ ): 1820, 1800 and 1758 cm- ¹ .

KMR spectrum (in CDCI ₃ ),

δ: 1.35 (s, 3);

1.74 (s, 3);

2.32 (s, 3); ι ο

4.55 (s, 2);

4.67 (s, 1);

5.17 (d, 1, J = 4.5 Hz);

6.12 (q, 1st) = 11 Hz and J = 4.5 Hz);

6.98 (s, 5).

(b) 2.2 g (5 mmol) of anhydride of phenoxymethylpenicillin sulfoxide and acetic acid are dissolved in 30 ml of dioxane. After adding 3 ml (11.7 mmol) of N, O-bis (trimethylsilyl) acetamide, 1.1 ml (15 mmol) of pyridine and 2 «0.6 ml of dichloromethane, which contains 3.6 mmol of a-picoline contains hydrobromide, the mixture is refluxed for 4 1/2 hours. The reaction mixture is then cooled to room temperature and, with stirring, poured into a mixture of 400 ml of a 0.75 M potassium phosphate buffer of pH 7 and 100 ml of ethyl acetate. After adjusting the pH to 7 with 4N potassium hydroxide solution, the mixture is placed in a separating funnel, shaken and left to stand. The aqueous phase is separated off, washed with 100 ml of ethyl acetate and, after the pH has been adjusted to 2, extracted twice with 4 η-sulfuric acid with 200 ml of ethyl acetate each time. After the reaction mixture has been dried over anhydrous magnesium sulfate, the ethyl acetate is evaporated off under reduced pressure. The dried residue (1.28 g) consists of 86 percent of 4 ³ -7-phenoxyacetamido-deacetoxycephalosporanic acid, as can be determined by CMR spectroscopy using 2,6-dichloroacetophenone as an internal standard. The yield is 63 percent of theory.

From this example it can be seen that the intermediate product formed as anhydride from the reaction mixture separated and how the anhydride formed in situ can be used for the ring expansion reaction.

Example 33

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 0.9 ml (9 mmol) of picoline and a solution of 3.0 mmol of hydrogen bromide in dioxane is added for 4 1/2 hours with the amounts of N, given in Table IV. O-bis (trimethylsilyl) acetamide is heated to reflux The total volume is 2.4 ml respectively. The determined by microbiological assay yields of iil ³ -7-phenylacetamido-desacetoxycephalosporanic acid are also shown in Table IV.

Table IV

Amount of N, O-bis (triniethylsilyl) acetamide

(mmol)

Yield to
/ l ³ -7-phenylacetamidodesacetoxycephalosporanic acid

45

50

55

65 Amount of N, O-bis (trimethylsilyl) acetamide

(mmol)

Yield of / J ³ -7-phenylacetamidodeacetoxycephalosporanic acid

82 85 85 70 46 21 0

From the table it can be seen that the highest yield of 85 percent when using about 9 to 10 moles of N, O-bis (trimethylsilyl) acetamide are obtained will.

Example 34

A cooled to 0 ^c C solution of 1060 mg (3 mmol) in Benzylpenicillinsulfoxid 0.72 ml (9 mmol) of pyridine and 20 ml of butyl acetate is treated with 0.24 ml (3 mmol) of acetyl bromide. After stirring for 30 minutes at room temperature, 2.1 g (9 mmol) of N, N'-bis (trimethylsilyl) urea are added, and the mixture is refluxed for 2½ hours.

The yield of 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is 77% of theory. Th.

Example 35

A mixture of 525 mg (1.5 mmol) benzylpenicillin sulfoxide, 0.12 ml (1.5 mmol) pyridine, 0.074 ml (1 mmol) acetyl bromide and 10 ml toluene is 5 hours at 100 ⁰ C with different amounts N, N ' -Bis- (trimethylsilyl) -urea heated. The yield of / 4 ³ -7-PhenylaCetamido-desacetoxycephalosporanic acid is determined microbiologically. The results are summarized in Table V:

Table V

N, N'-bis (trimethylsilyl) urea "

(mmol)

Silyl compound / sulfoxide molar ratio

yield

3.0
3.3
3.5
3.7
3.9
4.1
4.3
4.5

2.0
2.2
2.3
2.5
2.6
2.7
2.9
3.0

Example 36

79 79 83 85 83 90 87 84

60

0
56 A mixture of 525 mg (1.5 mmol) Benzylpenicillinsulfoxid, 0.24 ml (3 mmol) of pyridine, 0.04 ml (0.4 mmol) of phosphorus tribromide and 10 ml of toluene for 5 hours at 100 ⁰ C with various amounts of N , N'-bis- (trimethylsilyl) -urea heated. The yield of / 4 ³ -7-phenylacetamido-desacetoxycephalosporanic acid is determined microbiologically. The results are summarized in Table VI

22 40 224 yield Table VI N, N'-bis (trimethyl- Molar ratio SiIyI- (%) siIyl) -ureaT compound / sulfoxide 63 (mmol) 68 3.1 2.1 63 3.3 2.2 63 3.5 2.3 65 3.7 2.5 59 3.9 2.6 61 4.1 2.7 56 4.3 2.9 4.5 3.0

Claims (2)

Patent claims: Ί. Process for the preparation of 4 ³ -7-acylamido-3-methyIcephem-4-carboxylic acids by rearrangement of the corresponding 6-acylamidopenicillanic acid sulfoxides, the carboxyl group of which is protected, at elevated temperatures under acidic conditions and subsequent cleavage of the carboxyl protective groups, characterized in that one a) in a manner known per se, a 6-acylamidopenicillanic acid sulfoxide as the free acid in an anhydrous organic solvent with a halide of the general formula R _{2 is} reacted in which hai is a chlorine or bromine atom and R _{2 is} a group of the general formula \ ¹ N \ M ₁ - R ₄ -Ge- R ₄ -Si- R _4- R ₃ 2 - or R ₅ R ₆ represents and R ₃ , R «, R ₅ , Re, R3 ', R4' and R ₅ 'represent bromine atoms or R5 and R6 together represent an oxygen or sulfur atom or R3', R4 'and R5' represent a methyl or ethyl group , R _{7 is} a methyl, ethyl, trichloromethyl or phenyl group, Mi is a Bc, aluminum or phosphorus atom and M _{2 is} a phosphorus or tungsten atom, or R _{2 is} the group SOBr or CO — CO — Br and b) the acid anhydride obtained in the presence of N, O-bis (trimethylsilyl) acetamide,
N, N'-bis (trimethylsilyl) urea,
Hexamethyldisilazane, N ₁ O-bis (trimethylsilyr) -trifluoroacetamide, N-methyl-N-trimethylsilylacetamide or
N-methyl-N-trimethylsilyl trifluoroacetamide
Reacts at temperatures of 50 to 160 ° C with hydrogen chloride, hydrogen bromide, p-toluenesulfonic acid or picric acid or a ¹ ) converts the 6-acylamidopenicillanic acid sulfoxide as the free acid directly according to b), and in a manner known per se c) hydrolyzed the obtained 4 ^3- cephem compound and d) the obtained zl ³ -7-acylamido-3-methylcephem-4-carboxylic acid or an alkali metal or amine salt thereof is isolated. 2. The method according to claim 1, characterized in that step a), a ¹ ) or b) in the presence of an excess of Hexamethylenetetramine, diphenylamine, aniline,
N-methylaniline, dimethylaniline, pyridine,
Λ-picoline, 3-methylpyridine,
to 4-methylpyridine, 2,3-dimethylpyridine, 2,6-dimethylpyridine, 2-ethylpyridine,
2-propylpyridine, 4-benzylpyridine,
2-dimethylaminopyridine, 1,3,5-collidine,
Quinoline, isoquinoline, 3-methylisoquinoline,
j5 pyrazole, imidazole or N-methylimidazole, based on the amount of acid used.